WO2017021969A1 - Dérivé de pyrazole pyrimidine et utilisations de celui-ci - Google Patents

Dérivé de pyrazole pyrimidine et utilisations de celui-ci Download PDF

Info

Publication number
WO2017021969A1
WO2017021969A1 PCT/IL2016/050852 IL2016050852W WO2017021969A1 WO 2017021969 A1 WO2017021969 A1 WO 2017021969A1 IL 2016050852 W IL2016050852 W IL 2016050852W WO 2017021969 A1 WO2017021969 A1 WO 2017021969A1
Authority
WO
WIPO (PCT)
Prior art keywords
branched
straight
compound according
compound
alkyl
Prior art date
Application number
PCT/IL2016/050852
Other languages
English (en)
Inventor
Yinon Ben Neriah
Guy BRACHYA
Ido BURSTAIN
Waleed MINZEL
Irit SNIR-ALKALAY
Joseph Vacca
Dansu Li
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2018525826A priority Critical patent/JP7083309B2/ja
Priority to PL16753709T priority patent/PL3331877T3/pl
Priority to KR1020187006128A priority patent/KR102698366B1/ko
Priority to LTEPPCT/IL2016/050852T priority patent/LT3331877T/lt
Priority to RS20211558A priority patent/RS62728B1/sr
Priority to HRP20211949TT priority patent/HRP20211949T1/hr
Priority to AU2016304464A priority patent/AU2016304464B2/en
Priority to EP16753709.1A priority patent/EP3331877B1/fr
Priority to MX2018001395A priority patent/MX2018001395A/es
Priority to NZ739511A priority patent/NZ739511B2/en
Priority to US15/748,536 priority patent/US10376511B2/en
Priority to CN201680059148.XA priority patent/CN108137562B/zh
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd
Priority to SI201631426T priority patent/SI3331877T1/sl
Priority to RU2018107668A priority patent/RU2735522C2/ru
Priority to CA2994644A priority patent/CA2994644A1/fr
Priority to DK16753709.1T priority patent/DK3331877T3/da
Priority to ES16753709T priority patent/ES2901349T3/es
Publication of WO2017021969A1 publication Critical patent/WO2017021969A1/fr
Priority to ZA2018/00671A priority patent/ZA201800671B/en
Priority to IL257282A priority patent/IL257282B/en
Priority to HK18115603.7A priority patent/HK1256535A1/zh
Priority to US16/538,550 priority patent/US10960003B2/en
Priority to AU2021200839A priority patent/AU2021200839A1/en
Priority to US17/215,959 priority patent/US11925641B2/en
Priority to CY20211101124T priority patent/CY1124898T1/el

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention provides pyrazole pyrimidine derivatives and uses thereof in methods of treating malignant disease and disorders and methods for treating inflammatory diseases and disorders.
  • the casein kinase 1 family (CKl, or CKl) are serine/threonine kinases with six members (isoforms) in humans: ⁇ , ⁇ , ⁇ 2, ⁇ 3, ⁇ and ⁇ . They differ in length and sequence of the N-terminal (9- 76 amino acids) and especially the C-terminal (24- 200 amino acids) non-catalytic domain (Schittek and Sinnberg, Molecular Cancer 2014, 13:231).
  • CK15 and CKle are 98% identical in their kinase domain and 53% identical in their C-terminal regulatory domain (Fish KJ et al. J Biol Chem 1995, 270:14875- 14883). Whereas, there is some redundancy with respect to CKl substrate phosphorylation, most CKl isoforms have distinct biological roles.
  • the wide range of CKl substrates shows that the CKl family members are involved in multiple cellular processes, from regulation of membrane trafficking, cytokinesis, vesicular transport, ribosome biogenesis, DNA repair, signal transduction pathways, apoptosis and in the circadian rhythm (Knippschild U et al. Cell Signal 2005, 17:675-689; Cheong JK and Virshup DM. Int J Biochem Cell Biol 2011, 43:465-469; Zemp I, et al. J Cell Sci 2014, 127:1242-1253).
  • CKl a plays a role in the mitotic spindle formation during cell division and in DNA repair mechanisms and participates in RNA metabolism (Knippschild U et al. Cell Signal 2005, 17:675-689). It contributes to the activation of mTOR via sustained degradation of the endogenous mTOR inhibitor DEPTOR (Duan S et al. Mol Cell 2011, 44:317-324).
  • CKla has a major role in regulation of the Wnt/ -catenin signaling pathway. The inventors of this application have shown that CKla is a key component of the ⁇ -catenin destruction complex.
  • CKla phosphorylates ⁇ - catenin at serine residue S45, which is necessary for the priming phosphorylation of another kinase, GSK3 (Amit et al. Genes Dev. 2002 16: 1066-1076).
  • ⁇ -catenin phosphorylation by GSK3 at residues T41, S37 and S33 generates a ubiquitination degron, recruiting the E3 SCF-P-TrCP, leading to the ubiquitination and degradation of ⁇ -catenin (Clevers H and Nusse R Cell 2012, 149: 1192-1205).
  • CKla ablation causes several tumor-suppressor pathways, among which are DNA damage response (DDR), cellular senescence and p53 pathway activation (Elyada E et al. Nature 2011, 470: 409-413, Pribluda A et al. Cancer Cell 2013, 24: 1-5).
  • DDR DNA damage response
  • CKla ablation results in the induction of a new type of an inflammatory response, denoted parainflammation, which is confined to the epithelium, with no common signs of inflammatory response (inflammatory cell infiltration, calor, rubor, tumor and dolor) (Pribluda A et al.
  • Cancer Cell 2013, 24: 1-5 Lasry A and Ben-Neriah Y 2015, Trends in Immunology, Vol. 36: 217-228).
  • Parainflammation cooperates with WT p53 02429524H5-01 activation in suppressing tumorigenesis, yet switches to a tumor promoting mechanism in the absence of functional p53 Pribluda A et al. Cancer Cell 2013, 24: 1-5, Aran et al., Genome Biol. 2016 Jul 8;17(1):145).
  • CKla is a major regulator of p53
  • the inventors have also found that the combined ablation of CKI5 and CKle in the gut epithelium also results in p53 activation, which may synergize with CKla-induced p53 activation.
  • IRAKI was identified as a therapeutic target for MDS, and certain subsets of AML and triple negative breast cancer (Garrett W. Rhyasen et al, 2013, Cancer Cell 24, 90-104, Rhyasen GW, Bolanos L, Starczynowski DT, 2013, Exp Hematol. 41:1005-7, Zhen Ning Wee et al, 2015, NATURE COMMUNICATIONS, 6:8746).
  • IRAKI mRNA is over-expressed in -20-30% of MDS patients and the IRAKI protein is dramatically over-expressed and is hyperactivated in a majority of MDS marrow sample examined.
  • IRAKI is a serine/threonine kinase that mediates signals elicited from Tolllike receptor (TLR) and Interleukin-1 Receptor (IL1R). Following receptor activation, IRAKI becomes phosphorylated which then leads to recruitment of TRAF6, resulting in TRAF6 activation of NF- ⁇ and JNK pathways.
  • TLR Tolllike receptor
  • IL1R Interleukin-1 Receptor
  • IRAKI/4 Inhibitor Small molecule inhibitors targeting IRAKI (IRAKI/4 Inhibitor, Amgen Inc.) have been originally developed for autoimmune and inflammatory diseases. Given that IRAKI is hyperactivated (i.e., phosphorylated) in MDS but not normal marrow cells, Starczynowski and colleagues showed that IRAK- Inhibitor treatment (IRAKI/4, Amgen) and the knockdown of IRAKI resulted in dramatic impairment of MDS cell proliferation, progenitor function, and viability in vitro and in vivo.
  • TNBC triple negative breast cancer cells
  • IRAKI overexpression confers triple negative breast cancer cells (TNBC) growth advantage through NF-KB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAKI dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAKI .
  • Paclitaxel treatment of TNBC cells induces strong IRAKI phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel 02429524H5-01 treatment.
  • Pharmacologic inhibition of IRAKI was able to reverse paclitaxel resistance by triggering massive apoptosis.
  • IRAKI was also found to be a DEK transcriptional target and is essential for head and neck cancer cell survival (Adams AK et al. Oncotarget. 2015, 22; 6(41): 43395 - 43407) and also as potential target in the treatment of inflammatory- and immune -related disorders (Bahia MS et al. Cell Signal. 2015 Jun;27(6):1039-55).
  • the present invention provides a compound having the general formula (I), including any stereoisomer or salt thereof:
  • Ri and R2 are each independently selected from H, straight or branched Ci - Cs alkyl, straight or branched Ci - C5 alkoxy, straight or branched Ci - C5 acyl, C5 - C15 aryl, C3 - C7 heteroaryl each optionally substituted by at least one of halide, hydroxyl, ester, ether, C5 - C15 aryl, C3 - C7 heteroaryl, and amide; or
  • Ci - C5 alkyl C5 - C15 aryl, C3 - C7 heteroaryl, hydroxyl, halide and cyano;
  • R3 and R4 are each independently selected from H, straight or branched Ci - Cs alkyl optionally substituted by at least one of halide, hydroxyl, alkoxy, C5 - C15 aryl, C3
  • R5 and R8 are each independently selected from H, halide, straight or branched Ci
  • R6 is selected from straight or branched Ci - C 8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - Cs alkynyl, C5 - C10 cycloalkyl, saturated or unsaturated 4 - 6 membered heterocyclyle; optionally substituted by at least one of straight or branched Ci - Cs alkyl, C3 - C7 cycloalkyl, 4 - 6 membered heterocyclyle, C5
  • Ci5 aryl C3 - C7 heteroaryl, halide, hydroxyl, Ci - C5 alkyl halide;
  • R7 is selected from straight or branched Ci - C 8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - Cs alkynyl; substituted by at least one C3 - C7 cycloalkyl, 4 - 6 membered heterocyclyle, C5 - C15 aryl, C3 - C7 heteroaryl, halide, hydroxyl, Ci - C5 alkyl halide.
  • the present invention provides a compound having the general formula (I), including any stereoisomer or salt thereof wherein:
  • Ri and R2 are each independently selected from H, straight or branched Ci - Cs alkyl, straight or branched C2 - Cs alkenyl, straight or branched C2 - Cs alkynyl, straight or branched Ci - C5 alkoxy, straight or branched Ci - C5 acyl, C5 - C15 aryl, C3 - C7 heteroaryl each optionally substituted by at least one of halide, hydroxyl, ester, ether, C5
  • R3 and R4 are each independently selected from H, straight or branched Ci - Cs alkyl, straight or branched C2 - Cs alkenyl, straight or branched C2 - Cs alkynyl, optionally substituted by at least one of halide, hydroxyl, alkoxy, ester, C5 - C 1 5 aryl, C3
  • R5 and Rs are each independently selected from H, halide, straight or branched Ci - C8 alkyl, straight or branched C2 - Cs alkenyl, straight or branched C2 - Cs alkynyl, optionally substituted by at least one halide (in some embodiments CF3);
  • R6 is selected from straight or branched Ci - C 8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - Cs alkynyl, C5 - C10 cycloalkyl, saturated or unsaturated 4 - 6 membered heterocyclyle; optionally substituted by at least one of straight or branched Ci - Cs alkyl, C3 - C7 cycloalkyl, 4 - 6 membered heterocyclyle, C5
  • Ci5 aryl C3 - C7 heteroaryl, halide, hydroxyl, Ci - C5 alkyl halid;
  • R7 is selected from straight or branched Ci - C 8 alkyl, straight or branched C2 - C8 alkenyl, straight or branched C2 - Cs alkynyl; substituted by at least one C3 - C7 cycloalkyl, 4 - 6 membered heterocyclyle, C5 - C15 aryl, C3 - C7 heteroaryl, halide, hydroxyl, Ci - C5 alkyl halide.
  • Ri and R2 are each independently selected from H, straight or branched Ci - Cs alkyl optionally substituted by at least one of halide, hydroxyl, ester and amide.
  • Ri and R2 are each independently selected from H, straight or branched Ci - C5 alkoxy optionally substituted by at least one of halide, hydroxyl, ester and amide.
  • Ri and R2 are each independently selected from H, Ci - C5 acyl, optionally substituted by at least one of halide, hydroxyl, ester,ether and amide.
  • Ri and R2 are each independently selected from H, C5 - Ci5 aryl, optionally substituted by at least one of halide, hydroxyl, ester,ether and amide.
  • At least one of Ri and R2 is H.
  • R4 is H. In some embodiments, R3 and R4 are H.
  • R5 is selected from H, CI and straight or branched Ci - C4 alkyl. In some embodiments, R5 is H. In some embodiments, Rs is selected from H, CI and straight or branched Ci - C4 alkyl. In some embodiments, Rs is H. In some further embodiment one of R5 or Rs is H (i.e. only one of R5 or Rs is H, in other words one of R5 or Rs is different than H).
  • R6 is selected from straight or branched Ci - Cs alkyl, C5
  • Cio cycloalkyl saturated or unsaturated 4 - 6 membered heterocyclyle
  • R7 is selected from straight or branched Ci - Cs alkyl, substituted by at least one C3 - C7 cycloalkyl, 4 - 6 membered heterocyclyle, C5 - C15 aryl, C3 - C7 heteroaryl, halide, hydroxyl, Ci - C5 alkyl halide.
  • R6 is selected from a straight or branched Ci - Cs alkyl, C5
  • Cio cycloalkyl 4 - 6 membered saturated heterocyclyle.
  • R7 is a straight or branched Ci - Cs alkyl substituted by at least one of C3 - C7 cycloalkyl and hydroxyl.
  • R6 is selected from straight or branched Ci - Cs alkyl, saturated or unsaturated 4 - 6 membered heterocyclyle, each optionally substituted by at least one of straight or branched Ci - Cs alkyl, C3 - C7 cycloalkyl, halide, hydroxyl, CF3.
  • R7 is a straight or branched Ci - Cs alkyl substituted by at least one C3 - C7 cycloalkyl.
  • Ri and R2 together with the nitrogen atom they are connected to form a 4 - 7 membered saturated ring.
  • Ri and R2 together with the nitrogen atom they are connected to form a 4 - 7 membered saturated ring including at least one of N or O (in addition to the N atom Ri and R2 are connected to).
  • Ri and R2 together with the nitrogen atom they are connected to form a 4 - 7 membered aromatic ring optionally including at least one of N or O (in addition to the N atom Ri and R2 are connected to).
  • the compound of the invention is selected from the following:
  • the compound of the invention is:4 5-01 some other emb
  • Ci - Cs alkyl should be understood to encompass a hydrocarbon saturated chain, which can be straight or branched, comprising 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • straight or branched C2— Cs alkenyl or "straight or branched C2 Cj alkenyl” should be understood to encompass a hydrocarbon chain having at least one double bond between any two carbon atoms in the chain, which can be straight or branched, comprising 2, 3, 4, 5, 6, 7, or 8 carbon atoms or 2, 3, 4, 5 carbon atoms, respectively.
  • straight or branched C2 - Cs alkynyl should be understood to encompass a hydrocarbon chain having at least one triple bond between any two carbon atoms in the chain, which can be straight or branched, comprising 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Ci - Cs alkoxy should be understood to encompass an -OR9 moiety wherein R9 is a straight or branched Ci - C5 alkyl.
  • halide should be understood to encompass any halogen radical selected from -F, -Br, -CI, -I.
  • Ci - Cj alkyl halide should be understood to encompass any straight or branched alkyl chain having between 1 to 5 carbon atoms being substituted by at least one halogen radical selected from -F, -Br, -CI, -I, at any point one the straight or branched chain.
  • alkyl halide includes one halogen; in other embodiments alkyl halide includes two halogen atoms (the same or different); in other embodimebts, alkyl halide includes three halogen atoms (the same or different) and so on.
  • hydroxy I should be understood to encompass -OH.
  • ether should be understood to encompass any of -R13OR14' or -OR15' wherein R 1 3 is selected from a straight or branched Ci - Cs alkylene and R 1 4' and R15' are each indpependantly selected from a straight or branched Ci - Cs alkyl.
  • Cj - C / j aryl should be understood to encompass any single or fused aromatic ring system comprising 5 to 7 carbon atoms. Examples include, but are not limited to phenyl, pentalenyl, naphatalenyl, anthracenyl, and any combinations thereof.
  • C3 - C7 heteroaryl should be understood to encompass any single or fused aromatic ring system comprising 5 to 7 carbon atoms and at least one heteroatom selected from N, O and S.
  • Examples include, but are not limited to furanyl, benzofuranyl, 02429524H5-01 isobenzofuranyl, pyrrolynyl, indolynyl, isoindolinyl, thiophenyl, banzothiophenyl, banzo[c]thiophenyl, imidazolyl, benzimidazolyl, purinyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiasolyl, benzothiazolyl, pyridinyl, auinolinyl, isoquinolinyl, pyromodinyl, quinzolinyl, pyridazinyl,
  • unsaturated or aromatic ring should be understood to relate to any ring that may be formed having 4, 5, 6, or 7 members including said nitrogen atom.
  • Said ring can be saturated, i.e. having all sigma bonds, unsaturated, i.e. having at least one double or at least one triple bond or any combinations thereof or aromatic, i.e. a ring system that possess aromatic character, cyclically conjugated molecular ring system with a stability (due to derealization ) significantly greater than that of a hypothetical localized structure (e.g. Kekule structure).
  • said ring can be selected from piperidinyl, pyrrolidinyl, azetidinyl and so forth.
  • said ring may be optionally substituted (on the ring system by substitution of an -H atom on said ring) with at least one of straight or branched Ci - C5 alkyl, hydroxyl, halide and cyano (-CN).
  • unsaturated or aromatic ring should be understood to relate to any ring that may be formed having 4, 5, 6, or 7 members including said nitrogen atom.
  • This ring forms a spiro bi-ring system with the cyclohexyl ring in the backbone of compound of formula I.
  • Said ring can be saturated, i.e. having all sigma bonds, or unsaturated, i.e. having at least one double or at least one triple bond or any combinations thereof.
  • the ring is an aromatic ring
  • Cs - Cm cycloalkyl or the term “C3 - C7 cycloalkyl” should be understood to encompass a saturated (i.e. the ring containing only sigma bonds between its members) hydrocarbon ring that comprises 5, 6, 7, 8, 9, or 10 carbon atoms or 3, 4, 5, 6, or 7 carbon atoms respectively.
  • saturated , unsaturated or aromatic 4 - 6 member ed heterocyclyle should be understood to encompass a saturated (i.e. the ring containing only sigma bonds between its members) , unsaturated or aromatic (i.e. the ring containing at least one double bond or at least one triple bond or any combinations thereof) ring containing 4, 5, or 6 members at least one of which is a heteroatom selected from N, O, S, P.
  • the compounds described herein may contain one or more chiral center, or may otherwise be capable of existing as two enantiomers or several diastereomers. Accordingly, the compounds of this invention include also mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. The compounds of this invention include also mixtures of diastereomers, as well as purified diastereomers or diastereomerically enriched mixtures.
  • the invention also includes any salt of a compound of formula (I), including any pharmaceutically acceptable salt, wherein a compound of the invention has a net charge (either positive or negative) and at least one counter ion (having a counter negative or positive charge) is added thereto to form said salt.
  • pharmaceutically acceptable salt(s) means those salts of compounds of the invention that are safe and effective for pharmaceutical use in mammals and that possess the desired 02429524H5-01 biological activity.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • the invention further provides a composition comprising at least one compound as defined herein above and below (according to general formula I).
  • the present invention also relates to pharmaceutical compositions comprising a compound of the subject invention in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents.
  • the auxiliaries must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant.
  • the compositions may be prepared by any method well known in the art of pharmacy.
  • Such methods include the step of bringing in association compounds of the invention or combinations thereof with any auxiliary agent.
  • auxiliary agent(s), also named accessory ingredient(s) include those conventional in the art, such as carriers,
  • 02429524H5-01 fillers fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents, antioxidants, and wetting agents.
  • compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste.
  • the compositions can further be processed into a suppository or enema for rectal administration.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.
  • compositions include aqueous and nonaqueous sterile injection.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use.
  • sterile liquid carrier for example water
  • transdermal administration e.g. gels, patches or sprays can be contemplated.
  • Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
  • the exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
  • the invention further provides a compound as defined herein above and below (according to general formula I), for use in therapy.
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, 02429524H5-01 the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan.
  • the amount of administration can be adjusted as the various factors change over time.
  • the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint).
  • binders e.g., gelatin, cellulose, gum tragacanth
  • excipients e.g., starch, lactose
  • lubricants e.g., magnesium stearate, silicon dioxide
  • disintegrating agents e.g., alginate, Primogel, and corn starch
  • sweetening or flavoring agents e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint
  • Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included.
  • the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.
  • the active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • Topical administration examples include nasal, bucal, mucosal, rectal, or vaginal applications.
  • the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols.
  • one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.
  • a special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.
  • Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al. (1984) /. Clin. Psych. 45:242-247 '.
  • Hydrogels can be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. In some instances, hydrogels are biodegradable or biosorbable.
  • hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al. (1984) /. Pharmaceut. Sci., 73: 1718-1720.
  • the invention further provides a compound as defined herein above and below (according to general formula I), for use in the inhibition of and least one of Casein kinase I (CKI) and Interleukin-1 receptor-associated kinase 1 (IRAKI).
  • CKI Casein kinase I
  • IRAKI Interleukin-1 receptor-associated kinase 1
  • a compound as defined herein above and below (according to general formula I) is used in the inhibition of CKI and IRAKI.
  • the use of a compound of the invention as defined herein above and below (according to formula I) enables the treatment of diseases, disorders, symptoms and conditions associated with at least one of CKI and IRAKI (or in some embodiments, both CKI and IRAKI).
  • the invention provides treatment of diseases, disorders, symptoms and conditions associated with the inhibition of at least one of CKI and IRAKI (or in some embodiments, both CKI and IRAKI).
  • the invention provides a compound as defined herein above and below (according to general formula I), for use in the inhibition of Interleukin- 1 receptor-associated kinase 1 (IRAKI).
  • IRAKI Interleukin- 1 receptor-associated kinase 1
  • the invention further provides a compound as defined herein above and below (according to general formula I), for use in the inhibition of Casein kinase I (CKI).
  • CKI Casein kinase I
  • Casein kinase I should be understood to encompass a protein kinases family that are serine/threonine- selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CKI isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, p53 activation and DNA transcription.
  • Interleukin-1 receptor-associated kinase 1 should be understood to encompass an enzyme encoded by the IRAKI gene which was found to be an important upstream regulator of the NF-kB pathway involved in disease pathways of hematological malignancies, such as multiple myeloma, MDS, leukemia and lymphoma, breast cancer, head and neck cancer, inflammatory and immune related disorders and others.
  • the invention further provides a compound as defined herein above and below (according to general formula I), for use in the treatment of a condition, symptom or disease associated with a malignant condition.
  • said malignant condition is cancer.
  • said cancer has either WT, or mutant p53 (mutations that deactivate p53 typical of cancer conditions).
  • said cancer is selected from leukemia, malignant melanoma, breast cancer, prostate cancer and colorectal cancer.
  • said cancer has WT p53.
  • the invention further provides a compound as defined herein above and below, for use in the treatment of cancer having WT p53, wherein said WT p53 is a biomarker for the said compound efficacy.
  • WT p53 serves as a measurable indicator to the efficacy of cancer treatment of the compound or composition comprising a compound of the invention.
  • the invnetion further provides a method of treating cancer having WT p53 in a subject in need thereof, wherein said WT p53 is a biomarker for the said compound efficacy
  • said use further comprises an induction of cancer immunotherapy response.
  • a compound or a composition comprising a compound of the invention provides both treatment of cancer (anti-tumor, anti-malignant activity) and cancer immunotherapy response.
  • said malignant condition is selected from hematological malignancies (Multiple Myeloma, Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), Melanoma and ER-negative breast cancer, Diffuse Large B cell lymphoma (DLBCL), Chronic Myelogenous Leukemia (CML), Chronic lymphocytic leukemia (CLL), head and neck cancer, and any combinations thereof.
  • MDS Multiple Myeloma
  • AML Acute Myeloid Leukemia
  • MDLBCL Diffuse Large B cell lymphoma
  • CML Chronic Myelogenous Leukemia
  • CLL Chronic lymphocytic leukemia
  • the invnetion provides a compound as defined herein above and below for use in inducing anti-tumor response.
  • said anti-tumor response comprises cancer immunotherapy response.
  • induced anti-tumor response should be understood to encompass any qualitative or quantitative chemotherapy of cancerous tumors.
  • cancer immunotherapy response should be understood to encompass any qualitative or quantitative cancer immunotherapy induction of the subject's own immune system to fight the cancerous cells.
  • immunotherapies can be categorized as active, passive or hybrid (active and passive), and are designed to exploit the fact that cancer cells often have molecules on their surface that can be detected by the immune system of a subject, known as tumour-associated antigens (TAAs); they are often proteins or other macromolecules (e.g. carbohydrates).
  • TAAs tumour-associated antigens
  • Passive immunotherapies enhance existing anti-tumor responses.
  • said cancer immunotherapy reasponse relates to the change in the expression of an immune checkpoint molecules on tumor cell, on an antigen presenting cell, on a T cell or on a Natural Killer (NK) cell.
  • NK Natural Killer
  • said cancer immunotherapy reasponse relates to the reduction in the expression of an immune checkpoint molecule on tumor cell that induces suppression of the anti-tumor activity of a T cell.
  • said cancer immunotherapy reasponse relates to the reduction in the expression of the checkpoint protein PD-L1. In some other embodiments, said immunotherapy response relates to the inhibition of PD-L1. In some further aspcts, a compound of the invention is used in a method of inhibiting PD-L1.
  • the invention further provides a compound as defined herein above and below (according to general formula I), for use in the treatment of an inflammatory and immune related disorder including a condition, symptom or disease associated therewith.
  • inflammatory and immune related disorders it should be understood to relate to any type of disorder (including conditions, symptoms and diseases associated therewith) that are treatable with Interleukin-1 receptor associated kinase inhibitors.
  • IRAKI is an indispensable element of IL- Rs and TLR pathways that can regulate the abnormal levels of cytokines, and therefore can be employed to manage immune- and inflammation-related disorders such as for example rheumatoid arthritis, inflammatory bowel disease, psoriasis, gout, asthma and cancer (Bahia MS et al. Cell Signal. 2015 Jun;27(6): 1039-55).
  • the invention further provides a method of treating a condition, symptom or disease associated with a malignant condition in a subject in need thereof, said method comprising the step of administering to said subject at least one compound as defined herein above and below (according to general formula I).
  • the invention further provides a method of inhibiting at least one of Casein kinase I (CKI) and Interleukin-1 receptor-associated kinase 1 (IRAKI) in a subject in need thereof comprising the step of administrating to said subject at least one compound as defined herein above and below (according to general formula I).
  • CKI Casein kinase I
  • IRAKI Interleukin-1 receptor-associated kinase 1
  • the invention provides a method of inhibiting Interleukin-1 receptor-associated kinase 1 (IRAKI) in a subject in need thereof comprising the step of administrating to said subject at least one compound as defined herein above and below (according to general formula I).
  • IRAKI Interleukin-1 receptor-associated kinase 1
  • a method of the invnetion further comprising inducing cancer immunotherapy response in said subject.
  • the invnetion provides a method for inducing an cancer immunotherapy response in a subject in need thereof, said method comprising the step of administering to said subject at least one compound as disclosed herein above and below.
  • the invention further provides a method of treating an inflammatory and immune related disorder including a condition, symptom or disease associated therewith; said method comprises administering to a subject in need thereof a compound as defined herein above and below (according to general formula I).
  • the invention also provides a method of inhibiting Casein kinase I in a subject in need thereof comprising the step of administrating to said subject at least one compound as defined herein above and below (according to general formula I).
  • Figures 1A and IB show a dose response of the indicated compounds of the invention (Fig. 1A compounds A36, A39, A6, A14, A35, A51, A29, A19-4, A41, A28, A42, A43, A46; Fig. IB compounds A30-1, A30-2, A51, A60, A64, A65) - screen in RKO colorectal cell line.
  • RKO cells were incubated for 16 hours at 37°C with indicated concentrations of the compounds and analyzed by Western Blot. Shown are ⁇ -catenin and p53 stabilization and phosphorylation of H2AX ( ⁇ 2 ⁇ ), a marker of DNA damage, indicative of CKIa kinase inhibition.
  • FIGS. 2A-2D show that the CKIa inhibitor A14 induces apoptosis of bone marrow cells isolated from CML blast crisis mice in a dose dependent manner (ex vivo).
  • Fig. 2A is a schematic representation of the experimental procedure; Incubation with A14 or DMSO for 8 hours.
  • Fig. 2B shows a dramatic reduction of the leukemic cell number following A14 treatment - a dose response curve.
  • Fig. 2C shows the increased percentage of apoptotic cells (Annexin5+/7AAD-) in a dose dependent manner.
  • Fig. 2D shows the increased percentage of total death (7AAD+) cells in a dose dependent manner.
  • FIG. 3A is a schematic representation of the experimental procedure, inoculating BM cells from a CML blast crisis mouse (GFP+ cells) to normal C57B1/6 mice and daily treatment (oral administration) with A14 or vehicle alone.
  • FIGS 4A-4F show the complete blood count at day 9 following A14 treatment of CML blast crisis mice:
  • Fig. 4D shows the absolute number of Granulocytes (Gran) in peripheral blood (10 9 /L).
  • Fig. 4E shows the red blood counts (RBC, 10 12 /L).
  • Fig. 4F shows the hemoglobin level (HGB, g/L).
  • Figure 5 shows representative photographs of blood smears from A14 treated compared to vehicle-treated CML blast crisis mouse at day 9 following BM transplantation.
  • Figure 6 shows a schematic representation of preparation of the AML mouse model.
  • Figures 7A-7D show the inhibitory effect of A14 on the progression of AML.
  • Fig. 7A is a schematic representation of the experimental procedures.
  • Fig. 7B demonstrates the percentage of GFP + leukocytes in peripheral blood (PB) of A14 treated compared to vehicle treated mice.
  • Figs. 7C and 7D shows representative Flow Cytometry analysis plots of the GFP + leukocytes in PB one day before (Fig. 7C) and three days (Fig. 7D) following A14 treatment.
  • FIGS 8A-8G show the complete blood count at day 9 after the treatment of AML mice with A14 of the invention.
  • Fig. 8 A shows the absolute number of white blood cells (WBC) in peripheral blood (10 9 /L).
  • Fig. 8B shows the absolute number of lymphocytes (Lymph) in peripheral blood (10 9 /L).
  • Fig. 8C shows the absolute number of monocytes (Mono) in peripheral blood (10 9 /L).
  • Fig. 8D shows the absolute number of granulocytes (Gran) in peripheral blood (10 9 /L).
  • Fig. 8E shows the red blood counts (RBC, 10 12 /L).
  • Fig. 8F shows the hemoglobin (g/L).
  • Fig. 8G shows platelets (PLT) in peripheral blood (10 9 /L).
  • Figure 9 shows representative photographs of blood smears from A14 compared to vehicle-treated AML mice at day 9 following the first A14 treatment.
  • Figure 10 shows IRAKI inhibition by the inhibitor compounds of the invention, A51 and A 14.
  • Cells were harvested and analyzed by Western blot. Blots were incubated with the following antibodies: Phospho-IRAKl (Thr209), (A1074, AssayBiothechnology; 1/1,000), Phospho- ⁇ / ⁇ (Serl76/180) (16A6, Cell Signaling; 1/1,000), IKKa (2682 , cell signaling; 1/1,1000), IKK ⁇ (2370 , cell signaling; 1/1,1000), Phospho-c-Jun (Ser 63) (9261, cell signaling; 1/I,1000),p53 (DO-1&1801 hybridoma mix; dilution of 1 :20 of supernatants from each), CKIa (C-19; 1/1,000; Santa Cruz Biotechnology) and phospho- histoneH2AX (S139; 1/1,000; Millipore).
  • Phospho-IRAKl Thr209), (A1074, AssayBiothe
  • FIGS 11A-11E relate to the experimental results achieved from a single-dose treatment of CKI inhibitor A51 in AML mice.
  • FIG. 11A schematically shows the preparation of AML mice and their treatment with A51 (20mg/Kg) at day 30 from induction of the desease (Leukemia inoculation).
  • Figs 1 IB - HE show the effect of A51 after 16hrs from treatment (in comparison with treatment with vehicle alone) in reduction of the total leukemia cells in the blood:
  • Fig. 11B shows the reduction in WBC in the peripheral blood (PB),
  • Fig. 11C shows the shrinking of the leukemic spleen and
  • Figs. 1 ID 02429524H5-01 and 1 IE show the reduction of proportion of leukemic blasts (GFP+ cells) in the peripheral blood (PB) and bone marrow (BM), respectively.
  • Figures 12A and 12B show pictures of spleen and bone from treated AML mice. Actual reduction in spleen size (splenomegaly) after treatment with A51, as disclosed above (Fig. 12A) and opaque bones turned to normal color following a single dose treatment (Fig. 12B).
  • Figures 13A-13E show the results of in vitro treatment effects of CKI inhibitors on AML cells isolated from the bone marrow of leukemic mice. Shown are the percentage of dead cells (7AAD+) and the effects of the inhibitors on the expression of the major immune checkpoint protein PD-L1 in the leukemic cells; Inhibitor treatment was in 10 or ⁇ for several time points (5 hours, - Fig. 13A, 6 hours - Figs. 13B and 13C, and 9 hours Figs. 13D and 13E).
  • Step 1 N, 0-Dimethylhydroxylamine hydrochloride (25.14 g, 257.69 mrnol, 1.72 eq), HATU (56.97 g, 149.82 mrnol, 1.00 eq) and TEA (45.48 g, 449.46 mrnol, 3.00 eq) were added to a solution of 2-cyclopropylacetic acid (15.00 g, 149.82 mrnol, 1.00 eq) in DCM (500 mL) at 0 °C, and then the mixture was stirred at 30 °C for 3 h. The resulting mixture was poured into water (500 mL). The aqueous washing phase was extracted with DCM (3*250 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column
  • Step 2 To a solution of 4-methyl-2-methylsulfanyl-pyrimidine (9.00 g, 64.19 mmol, 1.00 eq) in THF (500 mL) was added LDA (2 M, 48.46 mL, 1.51 eq) at -78°C. After stirring for 1 h, a solution of compound 2 (13.79 g, 96.29 mmol, 1.50 eq) in THF (500 mL) was added drop wise at -78 °C and then the reaction mixture was stirred at -78 °C for 4 h. Quenched with saturated aq.
  • Step 3 A solution of compound 4 (13.60 g, 61.18 mmol, 1.00 eq) in DMF-DMA (51.42 g, 2.45 mol, 40 eq) was stirred at 90 °C for 2 h. The solvent was removed in vaccum. The residue was purified by column chromatography on silica gel to give Core A (10.60 g, 36.30 mmol, 59.3% yield) as a yellow solid.
  • Step 4 A solution of Core A (10.60 g, 38.21 mmol, 1.00 eq) and hydrazine hydrate (6.75 g, 114.63 mmol, 3.00 eq) in ethanol (200 mL) was stirred at 90 °C for 3 h. The solvent was removed in vacuum. The residue was purified by column chromatography on silca gel to afford Core B (9.00 g, 35.81 mmol, 93.7% yield) as a light yellow solid.
  • Step 1 A solution of Core A (6.20 g, 22.35 mmol, 1.00 eq) and methylhydrazine (8.00 g, 69.46 mmol, 3.11 eq) in ethanol (100 mL) was stirred at 90 °C for 16 hrs. The solvent was removed in vacuum. The residue was purified by pre-HPLC (basic condition) to afford compound 5 (1.80 g, 6.84 mmol, 30.6% yield) as a yellow solid and the isomer 5A (2.00 g, 7.30 mmol, 32.6% yield) as a yellow oil.
  • Step 2 To a solution of compound 1 (1.50 g, 5.76 mmol, 1.00 eq) in DCM (20 mL) was added m-CPBA (2.98 g, 17.28 mmol, 3.00 eq) at 0 °C and stirred at 30 °C for 02429524H5-01 2 hrs. The resulting mixture was washed with NaHSCb (2 x 100 mL), saturate aq. NaHC03 (100 mL) and brine, dried over anhydrous Na2SO t, filtered and concentrated.
  • Step 1 Compound 35_6 was synthesized according to the procedure described in method A and it was obtained as a yellow solid after HPLC (TFA condition) purification. Yield: 17.1%;
  • Step 2 Compound 35_7 was synthesized according to the procedure described in method B and it was obtained as a yellow solid after purification through TLC. Yield: 57.8%;
  • Step 3 Compound A-35 was synthesized according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (4.0 eq) and it was obtained as a white solid. Yield: 19.7%
  • Step 1 Compound 36_6 was synthesized according to the procedure described in method A and it was obtained as a yellow oil after purification by prep_HPLC (TFA condition). Yield: 14.7%
  • Step 2 Compound 36_7 was made according to the procedure described in method B and it was obtained as a yellow solid after purification through column chromatography. Yield: 66.6%
  • Step 3 Compound A-36 was made according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (2.0 eq) and it was obtained as a whit solid after purification by prep_HPLC (TFA condition). Yield: 41.35%
  • Step 1 To a solution of Core B (700.00 mg, 2.84 mmol, 1.00 eq) in MeCN (14 mL) was added CS2CO3 (1.85 g, 5.68 mmol, 2.00 eq) at 0°C. After 30 min, 4-
  • Step 2 Compound 39_7 was made according to the procedure described in method B and it was obtained as a yellow solid after prep TLC purification. Yield: 72.6%
  • Step 3 Compound A-39 was made according to the procedure described in method C with iraws-cyclohexane-l ⁇ -diamine (3.0 eq) without DIEA and it was obtained as a yellow solid after purification through prep-HPLC (basic condition). Yield: 40.2%
  • Step 1 Compound 43_6 was synthesized according to the procedure described in method A and it was obtained as a yellow solid after purification by prep-HPLC (TFA condition). Yield: 17.9%
  • Step 2 Compound 43_7 was synthesized according to the procedure described in method B and it was obtained as a yellow solid after prep TLC purification. Yield: 79.6%
  • Step 3 Compound A-43 was synthesized according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (3.0 eq) and it was obtained as a white gum after purification by prep-HPLC (TFA condition). Yield: 24.7%;
  • Step 1 Compound 41_6 was synthesized according to the procedure described in method A and it was obtained as a yellow solid after purification by prep-HPLC (TFA condition). Yield: 13.1%
  • Step 3 Compound A-41 was synthesized according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (4.0 eq) and it was obtained as a white gummy solid after purification by prep HPLC (TFA condition). Yield: 17.2%
  • Step 1 Compound 42_6 was synthesized according to the procedure described in method A and it was obtained as a yellow solid after purification by prep HPLC (TFA condition). Yield: 21.4%
  • Step 2 Compound 42_7 was synthesized according to the procedure described in method B and it was obtained as a yellow solid after prep TLC purification. Yield: 83.2%
  • Step 3 Compound A-42 was synthesized according to the procedure described in method D and it was obtained as a white gummy solid after purification by prep HPLC (TFA condition). Yield: 51.5%
  • Step 2 To a solution of 38_2 (1.60 g, 6.39 mmol, 1.00 eq) in MeOH (15 mL) was added Pd(OH)2 (179.54 mg, 1.28 mmol, 0.20 eq). The mixture was stirred at 20°C under 3 ⁇ 4 (15psi) for 16 h. The mixture was filtered and the filtrate was concentrated to give 38_3 (450 mg, crude) as a colorless oil, which was used in the next step directly without purification.
  • Step 3 Compound 38_6 was made from Core A and compound 38_4 according to the same procedure as described for the synthesis of Core B and it was obtained as a yellow oil after purification by prep-HPLC (TFA condition). Yield: 40.3%
  • Step 4 Compound 38_7 was synthesized according to the procedure described in method B and it was obtained as a yellow solid after prep TLC purification. Yield: 56.1%
  • Step 5 Compound A-38 was synthesized according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (4.0 eq) and it was obtained as a yellow solid after purification by prep HPLC (basic condition). Yield: 40%
  • Step 1 Compound A-14 was prepared according to the procedure described in method G and it was obtained as a yellow solid. Yield: 38.4%
  • Step 2 To the mixture of compound 19_2 (1.00 g, 3.53 mmol, 1.00 eq) in MeOH (10 mL) was added HCl/dioxane (4 M, 10 mL, 11.33 eq) at 0 °C and the reaction mixture was stirred at 10 °C for 16 hour. LCMS showed the consumption of reactant. The reaction mixture was concentrated to give Amine-19 (700.00 mg, 3.19 mmol, 90.3% yield, HC1) as a white solid.
  • Step 1 Compound A19_4 was prepared according to the procedure described in method E with amine-19 (4 eq) and DIEA (4 eq) and it was as a white solid after purification by prep HPLC (basic condition). Yield: 72.2%
  • Step 3 To the mixture of 19_5 (330.00 mg, 890.81 ⁇ , 1.00 eq) in THF (500 ⁇ L) was added BH3 (1M, 7.13 mL, 8.00 eq) and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was cooled to 15 °C and poured into MeOH (20 mL). The mixture was concentrated. The crude product was purified by Pre-HPLC (basic condition) to give A-19 (23.00 mg, 64.52 ⁇ , 7.2% yield, 100% purity) as a white solid.
  • Step 1 Compound 27_2 was made according to the procedure descibed in method E with amine-27 (1.0 eq) and DIEA (10 eq) at 160°C for 6 h and it was obtained as a yellow solid after purification by prep HPLC (TFA). Yield: 41.1%
  • Step 2 To a solution of 27_2 (100.00 mg, 234.44 ⁇ , 1.00 eq) in THF (4.00 mL) was added L1AIH4 (26.69 mg, 703.32 ⁇ , 3.00 eq) at 0°C. The mixture was stirred at 70°C for 3 h. The mixture was cooled to 0°C and then quenched with aq.NH4Cl (3 drops). The resulting solution was dried over Na2S04 and then concentrated. The residue
  • Step 3 To a solution of 27_Boc (30.00 mg, 68.09 ⁇ , 1.00 eq) in DCM (100 ⁇ > was added HCl/dioxane (4 M, 85 ⁇ L ⁇ , 5.00 eq) in one portion at 0°C and the mixture was stirred at 15 °C for 5 h. The reaction mixture was concentrated to give A-27 (12.00 mg, 30.88 ⁇ , 45.35% yield, 97% purity, HC1) as a light yellow solid. Yield: 45.4%
  • Step 1 To a mixture of 29_l (658.25 mg, 3.07 mmol, 1.0 eq) and 2- methoxy acetyl chloride (500 mg, 4.61 mmol, 1.5 eq) in DCM (5 mL) was added DIEA (310.82 mg, 3.07 mmol, 1.00 eq) in at 0°C. Then the reaction mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography to give 29_2 (490.00 mg, 1.71 mmol, 55.7% yield) as a white solid.
  • Step 2 Compound 29-2 was deprotected in a similar manner as shown in step 3 of the synthesis of A27 and Amine-29 was obtained as a white solid. Yield: 91.9% 02429524H5-01 1H NMR (CD3OD, 400MHz) 4.05 (s, 1H), 374 (s, 2H), 3.70 - 3.69 (m, 1H), 3.36 (s, 3H), 3.28-3.27 (m, 1H), 3.09-3.07 (m, 1H), 2.07 - 2.04 (m, 2H), 1.94 - 1.92 (m, 2H), 1.56 - 1.40 (m, 4H)
  • Step 1 A mixture of 47_1 (200.00 mg, 933.27 ⁇ , 1.00 eq), 1, 5-diiodopentane (302.32 mg, 933.27 ⁇ , 1.00 eq) and K2CO3 (515.95 mg, 3.73 mmol, 4.00 eq) in MeCN (10 mL) was stirred at 90 °C for 16 hours. The mixture was filtered and the filtrate was concentrated to give 47_2 (300 mg, crude) as a white solid and it was used in next step directly.
  • Step 2 Crude 47_2 was deprotected in a similar manner as shown in step 3 of the synthesis of A27 and amine-47 was obtained as a white solid.
  • Compound A-48 was prepared according to the procedure described in method
  • Step 1 A solution of 2-cyclobutylacetonitrile (1.00 g, 10.51 mmol, 1.00 eq) in HCl (6 M, 10.00 mL, 5.71 eq) was stirred at 120°C for 16 h. The mixture was diluted with water (50 mL) and extracted with EA (20 mL*2). The combined organic layer was washed with water (40 mL), dried and concentrated to give 45_1 (750 mg, 6.57 mmol, 62.5% yield) as a colorless liquid
  • Step 2-4 Compound 45_5 was synthesized in a similar manner as decribed for the synthesis of Core A in scheme 1.1.
  • Compound 45_2 was obtained as a colorless liquid.
  • Step 5-6 Compound 45_7 was synthesized in a similar manner as decribed for the synthesis of Core C in scheme 1.2.
  • Compound 45_7 was obtained as a yellow oil after purification by pre-TLC. Yield: 86.6% ;
  • Step 7 Compound A-45 was made according to the procedure described in method D with iraws-cyclohexane-l, 4-diamine (4.0 eq) and it was obtained as a yellow solid after purification by prep HPLC (basic condition). Yield: 21.9%;
  • Compound 46_2 was obtained as a colorless oil.
  • Step 1 To a solution of compound N-methylpyrazole (51_1, 8.00 g, 97.44 mmol, 1.00 eq) in THF (160 mL) was added drop-wise n-BuLi (2.5 M, 46.77 mL, 1.20 eq) at - 78°C. After the resulting mixture was stirred for 1 h at that temperature, the solution of cyclopropanecarbaldehyde (8.20 g, 116.93 mmol, 1.20 eq) in THF (80 mL) was added drop-wise. And then the reaction mixture was stirred at 20°C for 16 h.
  • Step 4 To a solution of compound 51_6 (3.00 g, 13.95 mmol, 1.00 eq) in THF (60 mL) was added n-BuLi (2 M, 10.46 mL, 1.50 eq) drop-wise at -78°C. After sitrring for 0.5h at that temperature, a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- 02429524 ⁇ 45-01 dioxaborolane (5.19 g, 27.90 mmol, 2.00 eq) in THF (6 mL) was added. The resulting mixture was warmed to 20°C and stirred for 0.5h.
  • Step 6 The reaction mixture of compound 51_9 (300.00 mg, 1.06 mmol, 1.00 eq) and iraws-cyclohexane-l, 4-diamine (484.17 mg, 4.24 mmol, 4.00 eq) in dioxane (4.5 mL) was stirred at 130°C for 2h under microwave. The mixture was filtered and concentrated. The crude was purified by prep-HPLC (HCl condition) to give A-51 (80.00 mg, 200.04 ⁇ , 18.9% yield, 99.3% purity, HCl) as a yellow solid.
  • Step 1 To a mixture of NaCN (13.81 g, 281.82 mmol, 1.40 eq) in DMSO (240 mL) was added 53_1 (30.00 g, 201.30 mmol, 22.56 mL, 1.00 eq) dropwise at 60°C. The mixture was ketp at 75 °C for 16hr. The mixture was cool down and diluted with water (500 mL). The solution was extracted with EtOAc (200 mL*3). The combined organic layers were washed with brine (100 mL*3) and dried. The organic layer was concentrated to give 53_2 (15.00 g, 157.66 mmol, 78.3% yield) as a light yellow liquid.
  • Step 2 A solution of 53_2 (15.00 g, 157.66 mmol, 1.00 eq) in HC1 (6 M, 150 mL, 5.71 eq) was stirred at 120°C for 16 hours. The mixture was diluted with water (500 mL) and extracted with EtOAc (200mL*2). The combined organic layers were washed with water (400 mL). The organic layer was dried and concentrated to give 53_3 (16.00 g, 140.18 mmol, 88.9% yield) as a colorless liquid.
  • Step 3 To a solution of 53_3 (16.00 g, 140.18 mmol, 1.00 eq) and N- methoxymethanamine (20.51 g, 210.27 mmol, 1.50 eq, HQ) in DCM (160 mL) was added CDI (45.46 g, 280.36 mmol, 2.00 eq) at 0°C in portions. The mixture was stirred
  • Step 4 To a solution of 53_4 (4.50 g, 32.09 mmol, 1.00 eq) in THF (225 mL) was added LDA (2 M, 24.07 mL, 1.50 eq) at -78°C. After stirred for 1 hr, a solution of 2- cyclobutyl-N-methoxy-N-methyl-acetamide (6.05 g, 38.51 mmol, 1.20 eq) in THF (120 mL) was added into it at -78°C.
  • Step 6 To a solution of 53_6 (800.00 mg, 2.75 mmol, 1.00 eq) in EtOH (12 mL) was added isopropylhydrazine (364.95 mg, 3.30 mmol, 1.20 eq, HC1) and TEA (333.93 mg, 3.30 mmol, 457.43 uL, 1.20 eq). The mixture was stirred at 90°C for 1 hr. The mixture was concentrated. The crude was purified by pre-HPLC(TFA) to give 53_7 (600.00 mg, 1.88 mmol, 68.5% yield, 95% purity) as a yellow oil.
  • m-CPBA 1.01 g, 4.96 mmol, 85% purity, 2.50 eq
  • Step 8 To a solution of 53_8 (500.00 mg, 1.50 mmol, 1.00 eq) in dioxane (7.5 mL) was added trans-cyclohexane-l,4-diamine (685.14 mg, 6.00 mmol, 4.00 eq). The mixture was stirred at 130°C for 2 hr in the microwave. The mixture was filtered and concentrated. The crude was purified by prep HPLC(base) and prep HPLC(HCl) to give A-53 (250.00 mg, 615.9 ⁇ , 41% yield, 99.8% purity, HC1) as a yellow solid.
  • Step 3 The reaction mixture of 56_2 (2.00 g, 12.18 mmol, 1.00 eq) and KOH (2.73 g, 48.72 mmol, 4.00 eq) in NH 2 NH 2 .H20 (2.57 g, 48.72 mmol, 2.49 mL, 95% purity, 4.00 eq) and diglycol (40 mL) was heated to 110 °C for 1.5 hr, then at 200°C for another 1 hour with Dean-Stark. The mixture was diluted with water (50 mL) and extracted with MTBE (50 mL*2). The combined organic layers were concentrated to give 56_3 (1.10 g, crude) as a colorless oil.
  • Step 5 To a solution of 56_4 (1.45 g, 6.33 mmol, 1.00 eq) in THF (29 mL) was added n-BuLi (2 M, 4.75 mL, 1.50 eq) at -78°C. After 30 min, 2-isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (2.36 g, 12.66 mmol, 2.59 mL, 2.00 eq) in THF (2.5 mL)
  • 02429524H5-01 was added to it.
  • the resulting mixture was warmed to 20°C and stirred for 0.5 hr.
  • the mixture was quenched with saturated NH4CI (50 mL) and extracted with EtOAc (100 mL).
  • Step 6 To a solution of 56_5 (500.00 mg, 1.81 mmol, 1.00 eq) in DME (10 mL) was added 4-chloro-2-methylsulfanyl-pyrimidine (290.79 mg, 1.81 mmol, 210.72 ⁇ , 1.00 eq), NA2C03 (2 M, 1.99 mL, 2.20 eq) and 4-ditert-butylphosphanyl- N,N- dimethyl-aniline;dichloropalladium (64.09 mg, 90.50 ⁇ , 64.09 ⁇ , 0.05 eq) under nitrogen. The resulting mixture was stirred at 85°C for 2 hr under nitrogen.
  • Step 8 The mixture of 56_7 (200.00 mg, 652.78 ⁇ , 1.00 eq) and trans- cyclohexane-l,4-diamine (298.17 mg, 2.61 mmol, 4.00 eq) in dioxane (3 mL) was stirred at 130°C for 2 hr in the microwave. The mixture was filtered and concentrated. The crude was purified by prep-HPLC(base) to give A-56 (50.00 mg, 144.85 ⁇ , 22.2% yield, 98.6 % purity) as a yellow solid.
  • Step 1 to Step 6 Intermediate 58_6 was synthesized from compound 51_3 in a manner similar as described for the synthesis of A-56.
  • Step 7 To a solution of 58_6 (300.00 mg, 656.89 ⁇ , 1.00 eq) in THF (300 ⁇ > was added TBAF.3H 2 0 (414.51 mg, 1.31 mmol, 2.00 eq) at 20°C. The mixture was stirred for 30 min. The mixture was filtered and concenrtrated. The crude product was purified by prep-HPLC(base) to give A-58 (27.00 mg, 76.89 ⁇ , 11.7% yield, 97.5% purity) as a yellow solid.
  • Step 1 To a solution of 60_1 (2.00 g, 9.22 mmol, 1.00 eq) in THF (40 mL) was added ZnCi2-Et20 (1 M, 11.06 mL, 1.20 eq) at 0°C under nitrogen protection. The mixture was stirred for 2 hours at 0°C. Methylsulfanylsodium (646.23 mg, 9.22 mmol, 02429524H5-01 - TO
  • Step 4 The mixture of 60_4 (200.00 mg, 555.02 ⁇ , 1.00 eq) and trans- cyclohexane-1, 4-diamine (253.51 mg, 2.22 mmol, 4.00 eq) in dioxane (3 mL) was stirred at 130°C for 2 hours under microwave. The mixture was filtered and the filtrate was
  • Step 1 To a solution of 64_1 (2.00 g, 9.29 mmol, 1.00 eq) in DCM (20 mL) were added TEA (1.88 g, 18.58 mmol, 2.58 mL, 2.00 eq) and methanesulfonyl chloride (1.06 g, 9.29 mmol, 719.03 ⁇ , 1.00 eq) at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with H2O (30 mL) and extracted with DCM (20 mL*2). The combined organic layers were dried and concentrated to give 64_2 (2.50 g, 8.52 mmol, 91.7% yield) as a white solid.
  • Step 2 To a solution of lH-pyrazole (195.25 mg, 2.87 mmol, 1.20 eq) in MeCN (7.00 mL) were added Cs 2 C0 3 (1.56 g, 4.78 mmol, 2.00 eq) and 64_2 (700.00 mg, 2.39 mmol, 1.00 eq). The mixture was stirred at 100 °C for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and concentrated. The residue was purified by pre- HPLC (basic condition) to give 64_ 3(200.00 mg, 732.25 ⁇ , 30.6% yield, 97.1% purity) as a yellow solid.
  • Step 3 To a solution of 64_3 (180.00 mg, 678.35 ⁇ , 1.00 eq) in DCM (2 mL) was added TFA (400.00 ⁇ ) at 0°C. The mixture was stirred at 20°C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with DCM (10 mL*2). The aqueous layer was lyophilizd to give amine-64 (180.00 mg, 633.91 ⁇ , 93. 5% yield, 98.3% purity, TFA) as colorless oil.
  • Step 4 To a solution of 51_9 (100.00 mg, 353.16 ⁇ , 1.00 eq) in DMSO (1.5 mL) were added amine-64 (95.48 mg, 529.74 ⁇ , 1.50 eq) and DIEA (182.57 mg, 1.41 mmol, 246.71 ⁇ ⁇ , 4.00 eq). The resulting mixture was stirred at 160°C for 3 hours, filtered and the mother liquid was concentrated. The residue was purified by pre-HPLC (basic condition) and then prep-HPLC (HCl condition) to give A-64 (10.00 mg, 23.42 ⁇ , 6.6% yield, 100% purity) as a yellow solid.
  • Step 2 and step 3 Compound A-68 was synthesized in a manner similar as described for the synthesis of compound A-64 as a yellow solid.
  • reaction was quenched with a.q NaHC03 (1 mL) and filtered.
  • the filtrate was purified by prep-HPLC (TFA and then basic condition) to give A-96 (7.00 mg, 13.10 umol, 11.6% yield, 97.5% purity) as a white solid.
  • Step 1 To a solution of compound 51_7 (800 mg, 3.05 mmol, 1.00 eq) in DME (16 mL) were added compound 2 (509.54 mg, 3.05 mmol, 1.00 eq), Na 2 C0 3 (2 M, 4.6 mL, 3.00 eq) and 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (108.04 mg, 152.50 ⁇ , 108 uL, 0.05 eq) under nitrogen. The resulting mixture was stirred at 85 °C for 2 hours under nitrogen. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL). The organic layer was concentrated to give compound 86_1 (1.20 g, crude) as a yellow oil.
  • Step 2 The mixture of compound 86_1 (1.10 g, 4.12 mmol, 1.00 eq) and compound 4 (1.88 g, 16.48 mmol, 4.00 eq) in dioxane (16 mL) was stirred at 130 °C for 8 hours under microwave. The mixture was filtered and concentrated. The residue was purified by pre-HPLC (HC1 condition) to give A-86 (1.30 g, crude) as a yellow solid. A- 86 (300 mg) was purified again by prep-HPLC (HC1 condition) to give A-86 (20.00 mg, 52.51 ⁇ , 12.1% yield, 100% purity, HC1) as a yellow solid.
  • RKO colorectal cells were incubated with 10 ⁇ of each of the compounds for 16 hours at 37°C. Cells were washed with PBS and cell pellets were incubated with ice cold protein lysis buffer containing protease inhibitor cocktail (1/200;
  • phosphatase inhibitors (20mM p-nitrophenyl phosphate (PNPP), 20mM ⁇ -glycerophosphate and 300nM okadaic acid).
  • Western blot analysis was performed by 02429524H5-01 means of standard techniques. Blots were incubated with antibodies detecting ⁇ -catenin (1/2,500; BD Transduction), p53 (DO-1&1801 hybridoma mix; dilution of 1 :20 of supernatants from each), CKIa (C-19; 1/1,000; Santa Cruz Biotechnology) and phospho- histoneH2AX (S139; 1/1,000; Millipore). Secondary antibodies were HRP-linked goat anti-mouse, goat anti-rabbit and rabbit anti-goat antibodies (all 1/10,000; Jackson). Blots were developed using ECL (GE Healthcare).
  • BM bone marrow
  • EasySep #18757 cKit expressing cells
  • SCF stem cell factor
  • mice were sacrificed and their BM cells were transferred to new sublethally irradiated WT hosts; each such transfer was termed disease generation.
  • the hosts were no longer sublethally irradiated prior to disease transfer.
  • Blast crisis development was readily detectable by a highly abnormal number of blast cells, more than 30% of white blood cells (WBC) in the peripheral blood (PB), and short time intervals between transfers.
  • WBC white blood cells
  • CKI inhibitor studies were performed on late generation diseases, in which PB blasts were easily detectable, with no host irradiation and a short generation time (up to 12 days). Mice were monitored daily for cachexia, weight loss, lethargy, and ruff coats, and moribund mice were sacrificed upon moribund.
  • a selective CKIa inhibitor (A 14) was administered by oral gavage once a day at a dose of 10 mg/kg, starting from 24h after BM transplantation (BMT) ( Figure 3 A).
  • the inhibitor was dissolved in 1% methyl cellulose with 0.1% Tween 80 and 0.2% Poly-ethylene glycol (Vehicle). Control mice were treated with the vehicle only.
  • BM bone marrow
  • the culture was infected with MSCV-MLL-AF9- IRES-GFP retrovirus construct containing supernatant medium for 4 hours, then growth medium was added and infected cells were incubated at 37°C for additional 24h. .
  • the culture was then injected I.V. into sub lethally irradiated (500 rad) mice.
  • mice Upon detectable steady increase of GFP expressing cells in the mice peripheral blood (checked by FACS analysis) and rise in leukocyte numbers and immature cells (detected by Wright-Giemsa stained blood films), mice were sacrificed and their BM was transferred (1 st BMT) to sublethally irradiated WT hosts.
  • mice Upon emergence of AML disease mice were sacrificed and 50,000 BM cells were transplanted (2 nd BMT) into WT host mice. GFP expressing cells were monitored in the peripheral blood and upon detecting >10% GFP + in PB (day 11 after BMT) mice were treated with A14 inhibitor (Figure 7A). A14 was administered
  • FACS analysis All assays were performed on BD's equipment: FACS caliber, FACS ARIA sorter or LSR II machines.
  • FACS caliber FACS caliber
  • FACS ARIA sorter LSR II machines.
  • LSR II machines LSR II machines.
  • cells were suspended in a 1% BSA/PBS buffer with 5 ⁇ EDTA. Cells were then analyzed by using Annexin V PE Apootosis Detection Kit (eBioscience), 7-AAD (TONBO biosciences) and PE anti- mouse CD274 (B7-H1, PD-L1) antibody (clone 10F.9G2, BioLegend); Assays were performed according to the manufacturer's instruction. Monoclonal antibodies specific for CD 16 and CD32 (Miltenyi Biotec) were used for blockade of Fc receptors before staining.
  • Peripheral venous blood was obtained from the mouse facial vein using standard techniques and analyzed using the auto hematology analyzer BC-2800 (Mindray) per manufacturer's instructions.
  • Table 1 provides quantified information for compounds of the invention in activation of p53 and DNA damage response (DDR) and ⁇ -catenin stabilization as an indicator of Wnt pathway activation.
  • p53 activation was determined according to the degree of protein stabilization in several Western blot assays (Western blot examples are shown in Figs 1 A and IB).
  • A43 stabilized p53 significantly above the non- treatment control at 6 ⁇ with no activity at 2 ⁇ (Fig 1A, lower right panel) and thus received an average value of + for p53 activation.
  • A35 started stabilizing p53 at 0.2 ⁇ , with maximal stabilization at ⁇ (Fig 1A, upper right panel) and thus received an average value of +++ for p53 activation.
  • + indicates low, yet significant activation at a compound concentration of 6 ⁇ ; +++ indicates maximal ⁇ -catenin or p53 stabilization at >2 ⁇ ; ++++ indicates maximal activation of p53 and DDR at >0.5 ⁇ , +++++ indicates maximal activation of p53 and DDR at >0.1 ⁇ .
  • RKO cells were incubated for 16 hours at 37°C with the indicated concentrations of compounds of the invention A51 ( ⁇ ) and A14 (2 ⁇ ) ( Figure 10). At the indicated time points, RKO were treated with TNFa (100 units/ml). Cells were harvested and analyzed by Western blot.
  • KINOMEscanTM is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed 02429524 ⁇ 45-01 ligand. The assay is performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound.
  • Table 3 shows the Kd measurements for the interaction of A14 (WXL-4085) and A51 (WXL-5846) with IRAKI
  • IRAKI as a superior target in a kinome scan shows zero binding of IRAKI to its target in the presence of the inhibitors.
  • Pyrazole pyrimidine compounds of the invention A51 and A14 showed excellent binding Kd to IRAKI.
  • the compounds also showed inhibition of IRAKI activation and inhibition of the activation of the IRAKI target IKK (Ikappa B kinase) in RKO cells (Western blot analysis). It is to be noted that compound A51 showed complete (100%) inhibition of phospho- (active) IRAKI at a concentration of 1 ⁇ in the RKO cell line.
  • 02429524H5-01 malignancies including among others multiple myeloma, MDS, leukemia and lymphoma, head and neck cancer and breast cancer).
  • AML mice Single-dose treatment effect of a CKI inhibitor in AML mice and PD-L1 expression.
  • AML mice were prepared by inoculating MLL-AF9 oncogene-transduced bone marrow cells to C57/BL6 mice.
  • MLL-AF9 fusion represents one of a poor prognosis human AML induced by chromosomal translocation.
  • 30 days after leukemia inoculation the recipient mice have high white blood cells (WBC) counts (xlO higher than a normal mouse), and harbor >95 leukemia blasts in the bone marrow and 50% of the peripheral WBC in these mice are AML blasts.
  • WBC white blood cells
  • Oral treatment with A51 (20mg/Kg) for 16hrs results in massive reduction of the total leukemia cells in the blood (Fig. 11B), shrinking of the leukemic spleen (Fig. 11C and Fig. 12A), 50% and >90% reduction of proportion of leukemic blasts (GFP+ cells) in the bone marrow and blood, respectively (Fig. 11D and Fig. HE).
  • Opaque bones turned to normal color following a single dose treatment (Fig. 12B).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des dérivés de pyrazole pyrimidine qui inhibent la Caséine kinase I (CKI) et/ou la kinase 1 associée au récepteur de l'interleukine -1 (IRAKI 1) et des procédés de fabrication de ces dérivés, des compositions les comprenant et leurs utilisations dans des méthodes de traitement d'affections et de pathologies malignes et des méthodes permettant de traiter des maladies et des troubles inflammatoires.
PCT/IL2016/050852 2015-08-04 2016-08-04 Dérivé de pyrazole pyrimidine et utilisations de celui-ci WO2017021969A1 (fr)

Priority Applications (24)

Application Number Priority Date Filing Date Title
SI201631426T SI3331877T1 (sl) 2015-08-04 2016-08-04 Derivat pirazol pirimidina in njegova uporaba
PL16753709T PL3331877T3 (pl) 2015-08-04 2016-08-04 Pochodna pirazolopirymidyny i jej zastosowania
RU2018107668A RU2735522C2 (ru) 2015-08-04 2016-08-04 Пиразолпиримидиновое производное и его применение
RS20211558A RS62728B1 (sr) 2015-08-04 2016-08-04 Derivat pirazol pirimidina i njegove upotrebe
HRP20211949TT HRP20211949T1 (hr) 2015-08-04 2016-08-04 Derivat pirazol primidina i njegove uporabe
AU2016304464A AU2016304464B2 (en) 2015-08-04 2016-08-04 Pyrazole pyrimidine derivative and uses thereof
EP16753709.1A EP3331877B1 (fr) 2015-08-04 2016-08-04 Dérivé de pyrazole pyrimidine et utilisations de celui-ci
MX2018001395A MX2018001395A (es) 2015-08-04 2016-08-04 Derivados de pirazol pirimidina y sus usos.
NZ739511A NZ739511B2 (en) 2016-08-04 Pyrazole pyrimidine derivative and uses thereof
US15/748,536 US10376511B2 (en) 2015-08-04 2016-08-04 Pyrazole pyrimidine derivative and uses thereof
CN201680059148.XA CN108137562B (zh) 2015-08-04 2016-08-04 吡唑嘧啶衍生物及其用途
JP2018525826A JP7083309B2 (ja) 2015-08-04 2016-08-04 ピラゾールピリミジン誘導体及びその使用
KR1020187006128A KR102698366B1 (ko) 2015-08-04 2016-08-04 피라졸 피리미딘 유도체 및 이의 용도
LTEPPCT/IL2016/050852T LT3331877T (lt) 2015-08-04 2016-08-04 Pirazolpirimidino dariniai ir jų panaudojimas
CA2994644A CA2994644A1 (fr) 2015-08-04 2016-08-04 Derive de pyrazole pyrimidine et utilisations de celui-ci
DK16753709.1T DK3331877T3 (da) 2015-08-04 2016-08-04 Pyrazolpyrimidinderivat og anvendelser deraf
ES16753709T ES2901349T3 (es) 2015-08-04 2016-08-04 Derivado de pirazol pirimidina y usos del mismo
ZA2018/00671A ZA201800671B (en) 2015-08-04 2018-01-31 Pyrazole pyrimidine derivative and uses thereof
IL257282A IL257282B (en) 2015-08-04 2018-01-31 Compounds 2-(4-aminocyclohexylamino)-4-(pyrazol-4-yl)pyrimidine
HK18115603.7A HK1256535A1 (zh) 2015-08-04 2018-12-05 吡唑嘧啶衍生物及其用途
US16/538,550 US10960003B2 (en) 2015-08-04 2019-08-12 Pyrazole pyrimidine derivative and uses thereof
AU2021200839A AU2021200839A1 (en) 2015-08-04 2021-02-10 Pyrazole pyrimidine derivative and uses thereof
US17/215,959 US11925641B2 (en) 2015-08-04 2021-03-29 Pyrazole pyrimidine derivative and uses thereof
CY20211101124T CY1124898T1 (el) 2015-08-04 2021-12-21 Παραγωγο πυριμιδινης πυραζολης και χρησεις αυτου

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562200846P 2015-08-04 2015-08-04
US62/200,846 2015-08-04
US201562268750P 2015-12-17 2015-12-17
US62/268,750 2015-12-17

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/748,536 A-371-Of-International US10376511B2 (en) 2015-08-04 2016-08-04 Pyrazole pyrimidine derivative and uses thereof
US16/538,550 Continuation US10960003B2 (en) 2015-08-04 2019-08-12 Pyrazole pyrimidine derivative and uses thereof

Publications (1)

Publication Number Publication Date
WO2017021969A1 true WO2017021969A1 (fr) 2017-02-09

Family

ID=56738143

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2016/050852 WO2017021969A1 (fr) 2015-08-04 2016-08-04 Dérivé de pyrazole pyrimidine et utilisations de celui-ci

Country Status (23)

Country Link
US (3) US10376511B2 (fr)
EP (1) EP3331877B1 (fr)
JP (1) JP7083309B2 (fr)
KR (1) KR102698366B1 (fr)
CN (1) CN108137562B (fr)
AU (2) AU2016304464B2 (fr)
CA (1) CA2994644A1 (fr)
CY (1) CY1124898T1 (fr)
DK (1) DK3331877T3 (fr)
ES (1) ES2901349T3 (fr)
HK (1) HK1256535A1 (fr)
HR (1) HRP20211949T1 (fr)
HU (1) HUE057607T2 (fr)
IL (1) IL257282B (fr)
LT (1) LT3331877T (fr)
MX (1) MX2018001395A (fr)
PL (1) PL3331877T3 (fr)
PT (1) PT3331877T (fr)
RS (1) RS62728B1 (fr)
RU (1) RU2735522C2 (fr)
SI (1) SI3331877T1 (fr)
WO (1) WO2017021969A1 (fr)
ZA (1) ZA201800671B (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018142393A1 (fr) * 2017-02-01 2018-08-09 Yissum Research Development Company Of The Hebrew Dérivés de n1 -(4-(5-(cyclopropylméthyl)-1 -méthyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine et composés apparentés en tant qu'inhibiteurs de ck1 et/ou d'iraki pour le traitement du cancer
WO2019155468A1 (fr) 2018-02-08 2019-08-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Composés hétéroaryle, compositions pharmaceutiques de ceux-ci, et leur utilisation thérapeutique
WO2020247345A1 (fr) * 2019-06-03 2020-12-10 Biotheryx, Inc. Sels cristallins non hygroscopiques d'un composé pyrazole, compositions pharmaceutiques et utilisation de ceux-ci
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2022204220A1 (fr) * 2021-03-24 2022-09-29 Biotheryx, Inc. Pyrazolylpyrimidines pour le traitement d'une tumeur solide maligne
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US20230053307A1 (en) * 2021-07-19 2023-02-16 Buddhist Tzu Chi Medical Foundation Method for preventing or treating skin disorders and conditions
TWI824617B (zh) * 2021-07-12 2023-12-01 佛教慈濟醫療財團法人 促進毛髮生長的方法
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2901349T3 (es) * 2015-08-04 2022-03-22 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd Derivado de pirazol pirimidina y usos del mismo
JOP20180011A1 (ar) 2017-02-16 2019-01-30 Gilead Sciences Inc مشتقات بيرولو [1، 2-b]بيريدازين
TWI721483B (zh) 2018-07-13 2021-03-11 美商基利科學股份有限公司 吡咯并[1,2-b]嗒𠯤衍生物
CN114127058B (zh) * 2019-07-04 2024-06-25 深圳国顺康医药科技有限公司 一种杂环化合物、其药物组合物及用途
TW202140460A (zh) * 2020-01-13 2021-11-01 美商拜歐斯瑞克斯公司 吡唑基嘧啶及其用途
WO2021155050A1 (fr) * 2020-01-29 2021-08-05 Biotheryx, Inc. Modulateurs de kinase, compositions pharmaceutiques et applications thérapeutiques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150094305A1 (en) * 2013-09-27 2015-04-02 Nimbus Iris, Inc. Irak inhibitors and uses thereof
WO2015058140A1 (fr) * 2013-10-18 2015-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs polycycliques de kinase cycline-dépendante 7 (cdk7)
US20150202205A1 (en) * 2011-11-04 2015-07-23 Jasco Pharmaceuticals, LLC Aminopyrimidine kinase inhibitors

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1343781B1 (fr) 2000-12-05 2008-09-03 Vertex Pharmaceuticals Incorporated Inhibiteurs de kinases c-jun n-terminales (jnk) et d'autres proteines kinases
US6884804B2 (en) 2001-05-16 2005-04-26 Vertex Pharmaceuticals Incorporated Inhibitors of Src and other protein kinases
GB0215844D0 (en) 2002-07-09 2002-08-14 Novartis Ag Organic compounds
EP1730122A2 (fr) 2004-03-30 2006-12-13 Taisho Pharmaceutical Co., Ltd Derives de pyrimidine et procedes de traitement lies a l'utilisation de ceux-ci
JP2007145819A (ja) 2005-10-28 2007-06-14 Tanabe Seiyaku Co Ltd 医薬組成物
WO2007129195A2 (fr) 2006-05-04 2007-11-15 Pfizer Products Inc. 4-pyrimidine-5-amino-pyrazoles
WO2007138277A1 (fr) 2006-05-26 2007-12-06 Astrazeneca Ab 2-carbocycloamino-4-imidazolylpyrimidines en tant qu'agents d'inhibition de la prolifération cellulaire
WO2009071701A1 (fr) 2007-12-07 2009-06-11 Novartis Ag Dérivés de pyrazole et leur utilisation comme inhibiteurs de kinases dépendantes des cyclines
ES2901349T3 (es) * 2015-08-04 2022-03-22 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd Derivado de pirazol pirimidina y usos del mismo
WO2019155468A1 (fr) 2018-02-08 2019-08-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Composés hétéroaryle, compositions pharmaceutiques de ceux-ci, et leur utilisation thérapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150202205A1 (en) * 2011-11-04 2015-07-23 Jasco Pharmaceuticals, LLC Aminopyrimidine kinase inhibitors
US20150094305A1 (en) * 2013-09-27 2015-04-02 Nimbus Iris, Inc. Irak inhibitors and uses thereof
WO2015058140A1 (fr) * 2013-10-18 2015-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs polycycliques de kinase cycline-dépendante 7 (cdk7)

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
ADAMS AK ET AL., ONCOTARGET, vol. 6, no. 41, 22 December 2014 (2014-12-22), pages 43395 - 43407
AMIT ET AL., GENES DEV., vol. 16, 2002, pages 1066 - 1076
ARAN ET AL., GENOME BIOL., vol. 17, no. 1, 8 July 2016 (2016-07-08), pages 145
BAHIA MS ET AL., CELL SIGNAL., vol. 27, no. 6, June 2015 (2015-06-01), pages 1039 - 55
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BROWN ET AL., ANN. REV. MED., vol. 39, 1988, pages 221 - 229
CHEONG JK; VIRSHUP DM., INT J BIOCHEM CELL BIOL, vol. 43, 2011, pages 465 - 469
CLEVERS H; NUSSE R, CELL, vol. 149, 2012, pages 1192 - 1205
DUAN S ET AL., MOL CELL, vol. 44, 2011, pages 317 - 324
ELYADA E ET AL., NATURE, vol. 470, 2011, pages 409 - 413
ELYADA ET AL., NATURE, vol. 470, 2011, pages 409 - 413
ELYADA ET AL., NATURE, vol. 470, no. 7334, 17 February 2011 (2011-02-17), pages 409 - 13
FABIAN, M.A. ET AL.: "A small molecule-kinase interaction map for clinical kinase inhibitors.", NAT. BIOTECHNOL., vol. 23, 2005, pages 329 - 336
FISH KJ ET AL., J BIOL CHEM, vol. 270, 1995, pages 14875 - 14883
GARRETT W. RHYASEN ET AL., CANCER CELL, vol. 24, 2013, pages 90 - 104
KARAMAN, M.W. ET AL.: "A quantitative analysis of kinase inhibitor selectivity", NAT. BIOTECHNOL., vol. 26, 2008, pages 127 - 132
KNIPPSCHILD U ET AL., CELL SIGNAL, vol. 17, 2005, pages 675 - 689
LASRY A; BEN-NERIAH Y, TRENDS IN IMMUNOLOGY, vol. 36, 2015, pages 217 - 228
O.J. SANSOM, O.J. ET AL., GENES DEV., vol. 18, 2004, pages 1385 - 1390
PHILLIPS ET AL., J. PHANNACEUT. SCI., vol. 73, 1984, pages 1718 - 1720
PRIBLUDA A ET AL., CANCER CELL, vol. 24, 2013, pages 1 - 5
PRIBLUDA ET AL., CANCER CELL, vol. 24, no. 2, 12 August 2013 (2013-08-12), pages 242 - 56
RHYASEN GW; BOLANOS L; STARCZYNOWSKI DT, EXP HEMATOL., vol. 41, 2013, pages 1005 - 7
WILSON ET AL., J. CLIN. PSYCH, vol. 45, 1984, pages 242 - 247
ZEMP I ET AL., J CELL SCI, vol. 127, 2014, pages 1242 - 1253
ZHEN NING WEE ET AL., NATURE COMMUNICATIONS, vol. 6, 2015, pages 8746

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110475771B (zh) * 2017-02-01 2022-09-02 耶路撒冷希伯来大学伊森姆研究发展有限公司 Ck1和/或irak1抑制剂、药物组合物和用于癌症治疗的治疗应用
CN110475771A (zh) * 2017-02-01 2019-11-19 耶路撒冷希伯来大学伊森姆研究发展有限公司 治疗癌症的ck1和/或irak1抑制剂n1-(4-(5-(环丙基甲基)-1-甲基-1h-吡唑-4-基)吡啶-2-基)环己烷-1,4-二胺衍生物和相关化合物
US11999721B2 (en) 2017-02-01 2024-06-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Pyrazole compounds and uses thereof
WO2018142393A1 (fr) * 2017-02-01 2018-08-09 Yissum Research Development Company Of The Hebrew Dérivés de n1 -(4-(5-(cyclopropylméthyl)-1 -méthyl-1 h-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine et composés apparentés en tant qu'inhibiteurs de ck1 et/ou d'iraki pour le traitement du cancer
US11072599B2 (en) 2017-02-01 2021-07-27 Biotheryx, Inc. Pyrazole compounds and uses thereof
AU2018215809B2 (en) * 2017-02-01 2021-12-23 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. N1 -(4-(5-(cyclopropylmethyl)-1 -methyl-1 H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as CK1 and/or IRAKI inhibitors for treating cancer
WO2019155468A1 (fr) 2018-02-08 2019-08-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Composés hétéroaryle, compositions pharmaceutiques de ceux-ci, et leur utilisation thérapeutique
CN111971280A (zh) * 2018-02-08 2020-11-20 耶路撒冷希伯来大学伊萨姆研究发展公司 杂芳基化合物、其药物组合物和其治疗用途
JP2021512922A (ja) * 2018-02-08 2021-05-20 イッサム リサーチ ディベロップメント カンパニー オブ ザ ヘブリュー ユニバーシティ オブ エルサレム エルティーディー． ヘテロアリール化合物、それらの医薬組成物、及びそれら治療的使用
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2020247345A1 (fr) * 2019-06-03 2020-12-10 Biotheryx, Inc. Sels cristallins non hygroscopiques d'un composé pyrazole, compositions pharmaceutiques et utilisation de ceux-ci
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2022204220A1 (fr) * 2021-03-24 2022-09-29 Biotheryx, Inc. Pyrazolylpyrimidines pour le traitement d'une tumeur solide maligne
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
TWI824617B (zh) * 2021-07-12 2023-12-01 佛教慈濟醫療財團法人 促進毛髮生長的方法
US20230053307A1 (en) * 2021-07-19 2023-02-16 Buddhist Tzu Chi Medical Foundation Method for preventing or treating skin disorders and conditions
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

Also Published As

Publication number Publication date
EP3331877A1 (fr) 2018-06-13
US20210251992A1 (en) 2021-08-19
ZA201800671B (en) 2020-05-27
CN108137562A (zh) 2018-06-08
RU2735522C2 (ru) 2020-11-03
DK3331877T3 (da) 2022-01-03
CY1124898T1 (el) 2023-01-05
ES2901349T3 (es) 2022-03-22
RU2018107668A3 (fr) 2020-01-13
LT3331877T (lt) 2022-01-10
SI3331877T1 (sl) 2022-02-28
NZ739511A (en) 2023-08-25
US20190365759A1 (en) 2019-12-05
JP2018525441A (ja) 2018-09-06
HK1256535A1 (zh) 2019-09-27
RU2018107668A (ru) 2019-09-05
IL257282B (en) 2021-06-30
KR102698366B1 (ko) 2024-08-26
EP3331877B1 (fr) 2021-09-22
RS62728B1 (sr) 2022-01-31
HUE057607T2 (hu) 2022-06-28
MX2018001395A (es) 2018-04-13
PT3331877T (pt) 2021-12-27
HRP20211949T1 (hr) 2022-03-18
AU2016304464B2 (en) 2020-11-19
KR20180043794A (ko) 2018-04-30
JP7083309B2 (ja) 2022-06-10
US10960003B2 (en) 2021-03-30
PL3331877T3 (pl) 2022-01-31
IL257282A (en) 2018-03-29
US10376511B2 (en) 2019-08-13
CA2994644A1 (fr) 2017-02-09
US11925641B2 (en) 2024-03-12
US20180214447A1 (en) 2018-08-02
AU2016304464A1 (en) 2018-02-22
AU2021200839A1 (en) 2021-03-04
CN108137562B (zh) 2021-11-30

Similar Documents

Publication Publication Date Title
AU2016304464B2 (en) Pyrazole pyrimidine derivative and uses thereof
CN112105385A (zh) Irak降解剂和其用途
WO2020206424A1 (fr) Agents de dégradation de stat et leurs utilisations
CN110872289A (zh) 作为IDO1和/或TDO抑制剂的新颖的8-取代的咪唑并[1,5-a]吡啶
AU2021238333A1 (en) STAT degraders and uses thereof
US11999721B2 (en) Pyrazole compounds and uses thereof
NZ739511B2 (en) Pyrazole pyrimidine derivative and uses thereof
CN101346371A (zh) 癌症治疗中用作酪氨酸激酶抑制剂的4-(3-氨基吡唑)嘧啶衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16753709

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15748536

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 11201800846S

Country of ref document: SG

WWE Wipo information: entry into national phase

Ref document number: MX/A/2018/001395

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2994644

Country of ref document: CA

Ref document number: 2018525826

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2016304464

Country of ref document: AU

Date of ref document: 20160804

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20187006128

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2016753709

Country of ref document: EP

Ref document number: 2018107668

Country of ref document: RU